ES2320002T3 - NITROXIDERIVADOS DE ANTIHIPERTENSORES PHARMACOS. - Google Patents

Abstract

A compound of general formula (I) A- (Y-ONO2) s and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, wherein s is an integer equal to 1 or 2; A is selected from the following residues of beta-adrenergic blockers of formula (II): ** see formula ** in which R1 is selected from the group consisting of: ** see formula ** R2 is selected from the group consisting of: - CH (CH3) 2, -C (CH3) 3 or ** see formula ** when the radical R 1 has been chosen from the formulas (IIo), (IIp), (IIt), (IIu), (IIv), (IIy) or (IIz), R2 is -CH (CH3) 2; when the radical R 1 has been chosen from the formulas (IIq), (IIs) or (IIw), R 2 is -C (CH 3) 3; when the radical R1 is (IIr), R2 is (IIIc); Z is H or is a group that can join Y selected from the group consisting of: -C (O) -, -C (O) O- or ** see formula ** in which R '' and R '' ' 'are the same or different, and are H or straight or branched C 1 -C 4 alkyl; Z 1 is H or a group -C (O) that can join Y; with the proviso that when s of formula (I) is 1, Z or Z1 is H; Y is a bivalent radical having the following meaning: a) - linear or branched C1-C20 alkylene which is optionally substituted with one or more of the substituents selected from the group consisting of halogen, hydroxyl, -ONO 2 or T atoms, in which T is -OC (O) (C 1 -C 10 alkyl) -ONO 2, -O (C 1-C 10 alkyl) -ONO 2; b) - cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with side chains T 1, in which T 1 is linear or branched alkyl with from 1 to 10 c atoms) ** see formula ** in which: n is an integer from 0 to 20, and n1 is an integer from 1 to 20; n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1; R 3 and R 4 are independently selected from H or CH 3; And 1 is -CH2- or - (CH2) na-CH = CH- in which na is an integer from 0 to 20; X1 is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH; with the proviso that: - when s of formula (I) is 1, Z is - (CO) - and in formula (IV) of the bivalent radical Y n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1; - when s of formula (I) is 1, Z is - (CO) - and in formula (IV) of the bivalent radical Y n2, n3, n5 are equal to 0, n4 is 1 then n and n1 are different from 1; d) ** see formula ** in which: n1 is an integer from 1 to 20; X1 is WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH; n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R5 and R5 '' R6 and R6 '' are independently selected from the group consisting of H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C (CH3) 2SH; when the bond between the CA and CB carbons is a double bond R5 and R6 or R6 '' and R5 '' are absent; with the proviso that when Y is selected from the bivalent radicals mentioned in c) -d), the group -ONO2 is linked to a group - (CH2) n1-; with the proviso that when s of formula (I) is 1 and Z is - (CO) - then the bivalent radical Y does not have the meanings in a), b) and d); e) ** see formula ** in which X2 is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20, n11 is an integer from 0 to 6, R 11 is H, CH3 or group nitroxyl; with the proviso that when in formula (I) s is 1, in formula (II) Z is - (CO) -, in formula (VI) of the bivalent radical Y n10a, n10, n12 are equal to 1 then X cannot be an oxygen atom; f) ** see formula ** in which: n8 is an integer from 0 to 10; n9 is an integer from 1 to 10; R 9, R 10, R 8, R 7 are the same or different, and are H or linear or branched C1-C4 alkyl; in which the group -ONO2 is linked to ** see formula ** in which n9 is as defined above; ** see formula ** Y 2 is a saturated, unsaturated or aromatic 5 or 6-membered heterocyclic ring, which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting of: ** see formula * *

Description

Nitroxiderivatives of drugs antihypertensors

The present invention relates to derivatives of β-adrenergic blockers. Plus particularly, the present invention relates to nitroxiderivatives of blockers β-adrenergic agents, to pharmaceutical compositions that contain them and their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine, headache, vascular diseases and elevated intraocular pressure.

Blockers are widely used β-adrenergic agents (β-blockers) in the treatment of hypertension and cardiovascular diseases including angina chest, arrhythmias, acute myocardial infarction, cardiomyopathy hypertrophic, congestive heart failure. Do they work blocking the effects of catecholamines at receptor sites in the heart, but they differ somewhat in their ability to block receptors in the blood vessels and lungs. The selective β-blockers have their main actions on the heart, some others are weak beta-preceptor stimulants while that still block the main actions of catecholamines, some block both β1 and 1 receptors β2 in the heart and those in the blood vessels and not they have no stimulating activity and some block others Catecholamine receptors that can lead to vascular effects additional on the blood vessels.

Several side effects are associated with this class of drugs such as muscle fatigue, alterations of the sleep, reduced heart rate, hypotension, cold in the limbs, bronchospasm in asthmatic patients, hypoglycemia, increase in plasma lipids. In addition, withdrawal should be avoided abrupt after long-term treatment with beta-blockers, because a increased system sensitivity β-adrenergic.

U.S. Patent No. 6,242,432 gives know formula derivatives A- (X_ {1} -NO_ {2}) to have antithrombotic activity, in which A is the rest of a blocker β-adrenergic, X_ {1} is a bridge of bivalent connection and t o is 1 or 2. The invention is limited to particular meanings of the bivalent connection bridge X_ {1}.

U.S. Patent No. 5,502,237 and the U.S. Patent No. 5,639,904 discloses derivatives of formula R 1 -Ar-O-CH 2 -CH (OH) -CH 2 -NH-CH (CH 3) 2 used for the treatment of cardiovascular conditions, in which R1 is a chain that has at least one nitroxyl group as substituent

U.S. Patent No. 4,801,596 gives know aminopropanol derivatives of the formula

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one

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that can be used for prophylaxis and / or treatment of heart disease and circulatory, in which R 3 is an alkyl or a radical nitroxyalkyl containing from 3 to 8 atoms of carbon.

An object of the present invention was provide new nitroxiderivatives of blockers β-adrenergic agents that have a profile Global pharmacological significantly improved compared to native β-blockers that can not only eliminate or at least reduce the side effects associated with their original compounds, but also have a tolerance and Enhanced pharmacological activity.

It has been surprisingly found that nitroxiderivatives of β-adrenergic blockers of the present invention have a better pharmacological activity and organ protection properties, effects enhanced as anti-inflammatory and renal functions. In addition, they are effective in other pathologies including atherosclerosis, diabetes, peripheral vascular diseases (PVD) and intraocular pressure high.

In particular, it has been recognized that nitroxiderivatives of β-adrenergic blockers of the present invention, unlike the compounds previously mentioned in the prior art, show a enhanced activity on the cardiovascular system and tolerance enhanced and can be used to treat or prevent hypertension, cardiovascular diseases, glaucoma, migraine, headache, vascular diseases and elevated intraocular pressure.

They are object of the present invention nitroxiderivatives of β-adrenergic blockers of general formula (I):

A- (Y-ONO2) s

and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, in which s is an integer equal to 1 or 2, preferably s is 2;

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A is selected from the following remains of β-adrenergic blocker of formula (II):

2

in the that

R_ {1} is selected from the constituted group by:

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3

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R2 is selected from the group consisting of: -CH (CH 3) 2, -C (CH 3) 3 or

4

when the radical R_ {has} chosen from the formulas (IIo), (IIp), (IIt), (IIu), (IIv), (IIy) or (IIz), R2 is -CH (CH 3) 2;

when the radical R_ {1} has been chosen from the formulas (IIq), (IIs) or (IIw), R2 is -C (CH 3) 3;

when the radical R1 is (IIr), R2 is (IIIc);

Z is H or is a group that can join Y selected from the group consisting of:

-C (O) -, -C (O) O- or

5

in which R 'and R' 'are equal or different, and are H or linear C 1 -C 4 alkyl or branched;

Z_ {1} is H or a group -C (O) - which can join Y;

with the proviso that when s of formula (I) is 1, Z or Z1 is H;

when s is 2, Z and Z1 are preferably -CO)-;

And it is a bivalent radical that has the following meaning:

to)

-

\ vtcortauna linear or branched C 1 -C 20 alkylene, preferably C 1 -C 10, which is optionally substituted with one or more of the substituents selected from the group consisting of: halogen, hydroxyl, -ONO_ atoms {2} or T, in which T is -OC (O) (C 1 -C 10 alkyl) - ONO 2, -O (C 1 -C 10 alkyl) - ONO_ {2};

b)

-

\ vtcortauna cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with side chains T 1, in which T 1 is linear or branched alkyl with from 1 to 10 carbon atoms, T_ 1 is preferably CH 3;

C)

6

quad

in which:

quad

n is an integer from 0 to 20, preferably n is an integer from 0 to 10, plus preferably n is 0,

quad

and n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1;

quad

R 3 and R 4 are independently selected of H or CH 3;

quad

Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20, preferably na is equal to 0;

quad

X_ {1} is WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is oxygen;

quad

with the condition of:

-

\ vtcortauna when s of formula (I) is 1, Z is - (CO) - and in formula (IV) of the bivalent radical Y n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1;

-

\ vtcortauna when s of formula (I) is 1, Z is - (CO) - and in formula (IV) of the bivalent radical Y n2, n3, n5 are equal to 0, n4 is 1 then n and n1 are different from 1;

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d)

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7

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quad

in which:

quad

n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

X_ {1} is -WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is sulfur;

quad

n6 is an integer from 1 to 20,

quad

n7 is an integer from 0 to 20,

quad

R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of: H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the link between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' are absent;

quad

with the proviso that when Y is selected from the bivalent radicals mentioned in c) -d), the group -ONO_ {2} is joined to a group - (CH 2) n 1 -;

quad

with the proviso that when s of formula (I) is 1 and Z is - (CO) - then the bivalent radical Y no it has the meanings in a), b) and d);

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and)

8

quad

where X_ {2} is O or S,

quad

n10a, n10 and n12 are integers independently selected from 0 to 20,

quad

n10a is preferably selected from 0 to 10,

quad

n10 and n12 are preferably selected from 1 up to 10, and

quad

n11 is an integer from 0 to 6, preferably from 0 to 4,

quad

R 11 is H, CH 3 or nitroxyl group, preferably R 11 is H,

quad

R 11a is CH 3 or nitroxyl group;

quad

with the proviso that when in formula (I) s is 1, in formula (II) Z is - (CO) -, in formula (VI) of bivalent radical Y n10a, n10, n12 are equal to 1 then X no it can be an oxygen atom;

F)

9

quad

in which

quad

n8 is an integer from 0 to 10;

quad

n9 is an integer from 1 to 10;

quad

R 9, R 10, R 8, R 7 are the same or different, and are H or linear C 1 -C 4 alkyl or branched, preferably R 9, R 10, R 8, R 7 they are H;

quad

in which the group -ONO_ {2} is united to

10

quad

in which n9 is as defined previously;

quad

Y2 is a 5 or 6 member ring saturated, unsaturated or aromatic heterocyclic, containing one or more heteroatom (s) selected from nitrogen, oxygen, sulfur,

quad

and is selected from the constituted group by

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eleven

12

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An embodiment of the present invention it comprises compounds of formula (I) in which s is 2, A is a moiety of β-adrenergic blocker of formula (II) as defined above:

Z is a group that can join Y selected of the group consisting of:

-C (O) -, -C (O) O- or

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13

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in which R 'and R' 'are equal or different, and are H or linear C 1 -C 4 alkyl or branched;

Z1 is -C (O) -;

preferably Z and Z1 are -CO)-;

And it is a bivalent radical that has the following meaning:

to)

-

\ vtcortauna linear or branched C 1 -C 20 alkylene, preferably C 1 -C 10, which is optionally substituted with one or more of the substituents selected from the group consisting of: halogen, hydroxyl, -ONO_ atoms {2} or T, in which T is -OC (O) (C 2 -C 10 alkyl) - ONO 2, -O (C 1 -C 10 alkyl) - ONO_ {2};

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b)

-

\ vtcortauna cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with side chains T 1, in which T 1 is linear or branched alkyl with from 1 to 10 carbon atoms, T_ 1 is preferably CH 3;

C)

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14

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quad

in which:

quad

n is an integer from 0 to 20, preferably n is an integer from 0 to 10, plus preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1;

quad

R 3 and R 4 are independently selected of H or CH 3;

quad

Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20, preferably na is equal to 0;

quad

X_ {1} is WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is oxygen;

d)

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fifteen

         \ vskip1.000000 \ baselineskip
      

quad

in which:

quad

n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

X_ {1} is WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is sulfur;

quad

n6 is an integer from 1 to 20, preferably n6 is 1,

quad

n7 is an integer from 0 to 20, preferably n7 is 1,

quad

R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of: H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the link between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' are absent;

quad

with the proviso that when Y is selected from the bivalent radicals mentioned in c) -d), the group -ONO_ {2} is joined to a group - (CH 2) n 1 -;

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and)

16

quad

in which

quad

X_ {2} is O or S,

quad

n10a, n10 and n12 are integers independently selected from 0 to 20,

quad

n10a is preferably selected from 0 to 10,

quad

n10 and n12 are preferably selected from 1 up to 10, and

quad

n11 is an integer from 0 to 6, preferably from 0 to 4,

quad

R 11 is H, CH 3 or nitroxyl group, preferably R 11 is H,

quad

R 11a is CH 3 or nitroxyl group;

F)

17

quad

in which

quad

n8 is an integer from 0 to 10;

quad

n9 is an integer from 1 to 10;

quad

R 9, R 10, R 8, R 7 are the same or different, and are H or linear C 1 -C 4 alkyl or branched, preferably R 9, R 10, R 8, R 7 they are H;

quad

in which the group -ONO_ {2} is united to

18

quad

in which n9 is as defined previously;

quad

Y2 is a 5 or 6 member ring saturated, unsaturated or aromatic heterocyclic, containing one or more heteroatom (s) selected from nitrogen, oxygen, sulfur,

quad

and is selected from the constituted group by

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19

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Another embodiment comprises compounds of formula (I) in which

s is 1,

A is a remainder of blocker β-adrenergic of formula (II) as it is defined above:

Z is H,

Z1 is -C (O) -;

And it is a bivalent radical that has the following meaning:

to)

-

\ vtcortauna linear or branched C 1 -C 20 alkylene, preferably C 1 -C 10, more preferably C 3 -C 6 which is optionally substituted with one or more of the substituents selected from the group consisting of: halogen, hydroxyl, -ONO2 or T atoms, in which T is -OC (O) (C1-C10 alkyl) -O2, -O (C_ alkyl {1} -C_ {10}) - ONO2;

b)

-

\ vtcortauna cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with side chains T 1, in which T 1 is linear or branched alkyl with from 1 to 10 carbon atoms, T_ 1 is preferably CH 3;

         \ newpage
      

C)

         \ vskip1.000000 \ baselineskip
      

twenty

         \ vskip1.000000 \ baselineskip
      

quad

in which:

quad

n is an integer from 0 to 20, preferably n is an integer from 0 to 10, plus preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1;

quad

R 3 and R 4 are independently selected of H or CH 3;

quad

Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20, preferably na is equal to 0;

quad

X_ {1} is WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is oxygen;

         \ vskip1.000000 \ baselineskip
      

d)

         \ vskip1.000000 \ baselineskip
      

twenty-one

         \ vskip1.000000 \ baselineskip
      

quad

in which:

quad

n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

X_ {1} is WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is sulfur;

quad

n6 is an integer from 1 to 20,

quad

n7 is an integer from 0 to 20,

quad

R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of: H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the link between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' are absent;

quad

with the proviso that when Y is selected from the bivalent radicals mentioned in c) -d), the group -CNO_ {2} is joined to a group - (CH 2) n 1 -;

         \ newpage
      

and)

22

quad

where X_ {2} is O or S,

quad

n10a, n10 and n12 are integers independently selected from 0 to 20,

quad

n10a is preferably selected from 0 to 10,

quad

n10 and n12 are preferably selected from 1 up to 10, and

quad

n11 is an integer from 0 to 6, preferably from 0 to 4,

quad

R 11 is H, CH 3 or nitroxyl group, preferably R 11 is H,

quad

R 11a is CH 3 or nitroxyl group;

F)

         \ vskip1.000000 \ baselineskip
      

2. 3

quad

in which

quad

n8 is an integer from 0 to 10;

quad

n9 is an integer from 1 to 10;

quad

R 9, R 10, R 8, R 7 are the same or different, and are H or linear C 1 -C 4 alkyl or branched, preferably R 9, R 10, R 8, R 7 they are H;

quad

in which the group -ONO_ {2} is united to

         \ vskip1.000000 \ baselineskip
      

24

quad

in which n9 is as defined previously;

quad

Y2 is a 5 or 6 member ring saturated, unsaturated or aromatic heterocyclic, containing one or more heteroatom (s) selected from nitrogen, oxygen, sulfur,

         \ newpage
      

quad

and is selected from the constituted group by

25

Another embodiment comprises compounds of formula (I) in which

s is 1,

A is a remainder of blocker β-adrenergic of formula (II) as it is defined above:

Z_ {1} is H,

Z is a group that can join Y selected of the group consisting of: -C (O) -, -C (O) O- or

26

in which R 'and R' 'are equal or different, and are H or linear C 1 -C 4 alkyl or branched; preferably Z is -C (O) -; And it is a radical bivalent that has the following meaning:

C)

27

quad

in which:

quad

n is an integer from 0 to 20, preferably n is an integer from 0 to 10, plus preferably n is 0, and n1 is an integer from 1 to 20, preferably from 1 to 10;

quad

n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1;

quad

R 3 and R 4 are independently selected of H or CH 3;

quad

Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20, preferably na is equal to 0;

quad

X_ {1} is WC (O) - or -C (O) W-, where W is oxygen, sulfur or NH, preferably W is oxygen; with the proviso that when Z is -C (O) -:

-

\ vtcortauna in the bivalent radical Y of formula (IV) n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1;

-

\ vtcortauna in the bivalent radical Y of formula (IV) n2, n3, n5 are equal to 0, n4 is 1 then n and n1 are different from 1;

and)

28

quad

where X_ {2} is O or S,

quad

n10a, n10 and n12 are integers independently selected from 0 to 20,

quad

n10a is preferably selected from 0 to 10,

quad

n10 and n12 are preferably selected from 1 up to 10, and

quad

n11 is an integer from 0 to 6, preferably from 0 to 4,

quad

R 11 is H, CH 3 or nitroxyl group, preferably R 11 is H,

quad

R 11a is CH 3 or nitroxyl group;

quad

with the proviso that when Z is -C (O) - and in formula (VI) of the bivalent radical Y n10a, n10, n12 are equal to 1 then X cannot be an oxygen atom;

F)

29

quad

in which

quad

n8 is an integer from 0 to 10;

quad

n9 is an integer from 1 to 10;

quad

R 9, R 10, R 8, R 7 are the same or different, and are H or linear C 1 -C 4 alkyl or branched, preferably R 9, R 10, R 8, R 7 they are H;

quad

in which the group -ONO_ {2} is united to

30

quad

in which n9 is as defined previously;

quad

Y2 is a 5 or 6 member ring saturated, unsaturated or aromatic heterocyclic, containing one or more heteroatom (s) selected from nitrogen, oxygen, sulfur,

quad

and is selected from the constituted group by

31

Preferred compounds are those of formula (I) in which

s is 1

A is a remainder of blocker β-adrenergic of formula (II) as it is defined above,

Z is H and Z1 is -C (O) -,

and the bivalent radical Y has the following meaning:

a) C 1 -C 10 alkylene linear, preferably alkylene C 3 -C 6;

C)

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32

         \ vskip1.000000 \ baselineskip
      

quad

in which the group -ONO_ {2} is attached to (CH2) n1;

quad

n, n2, n3, n4, n5 are equal to 0,

quad

n1 is 1 and the group - (CH2) n1 - is attached to the phenyl ring through [C] 2 or the [C] 3 or [C] 4; or

quad

n, n2, n5 are 1,

quad

n3 and n4 are equal to 0, and

quad

n1 is an integer from 1 to 10,

quad

Y1 is - (CH2) na -CH = CH- in which na is 0,

quad

X_ {1} is WC (O) - where W is oxygen and the WC (O) group is attached to the phenyl ring through the [C] 4,

quad

R 4 is CH 3 and the group (OR 4) is attached to the phenyl ring through [C] 3;

d)

         \ vskip1.000000 \ baselineskip
      

33

         \ vskip1.000000 \ baselineskip
      

quad

in which

quad

el -ONO_ {2} is joined to the group - (CH 2) n 1 -;

quad

n1 is an integer from 1 to 10, n6 and n7 are 1, X_ {1} is WC (O) - where W is sulfur,

quad

R 5, R 5 'and R 6' are H,

quad

R 6 is NHCOCH 3.

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Another group of preferred compounds are those of formula (I) in which s is 1,

A is a remainder of blocker β-adrenergic of formula (II) as it is defined above,

Z_ {1} is H and Z is -C (O) -, and

the bivalent radical Y has the following meaning:

         \ newpage
      

C)

3. 4

quad

in which the group -ONO_ {2} is attached to (CH2) n1;

quad

n, n2, n3, n4, n5 are equal to 0,

quad

n1 is 1 and the group - (CH2) n1 - is attached to the phenyl ring through [C] 2 or the [C] 3 or [C] 4; or

quad

n, n2, n5 are 1,

quad

n3 and n4 are equal to 0, and

quad

n1 is an integer from 1 to 10,

quad

Y1 is - (CH2) na -CH = CH- in which na is 0,

quad

X_ {1} is -WC (O) - where W is oxygen and the WC (O) group is attached to the phenyl ring through the [C] 4,

quad

R 4 is CH 3 and the group (OR 4) is attached to the phenyl ring through [C] 3;

d)

35

quad

in which

quad

X_ {2} is O or S, and n10a and n11 are 0, n12 is 1 and R 11 is H and the group -ONO 2 is attached to (CH2) n12.

         \ vskip1.000000 \ baselineskip
      

Another group of preferred compounds are those of formula (I) in which s is 2,

A is a remainder of blocker β-adrenergic of formula (II) as it is defined above,

Z_ {1} and Z are -C (O) -, and

the bivalent radical Y has the following meaning:

a) C 1 -C 10 alkylene linear, preferably alkylene C 3 -C 6;

C)

36

quad

in which the group -ONO_ {2} is attached to (CH2) n1;

quad

n, n2, n3, n4, n5 are equal to 0,

quad

n1 is 1 and the group - (CH2) n1 - is attached to the phenyl ring through [C] 2 or the [C] 3 or [C] 4;

quad

or n, n2, n5 are 1,

quad

n3 and n4 are equal to 0, and

quad

n1 is an integer from 1 to 10,

quad

Y1 is - (CH2) na -CH = CH- in which na is 0,

quad

X_ {1} is -WC (O) - where W is oxygen and the WC (O) group is attached to the phenyl ring through the [C] 4,

quad

R 4 is CH 3 and the group (OR 4) is attached to the phenyl ring through [C] 3;

d)

37

quad

in which

quad

el -ONO_ {2} is joined to the group - (CH 2) n 1 -;

quad

n1 is an integer from 1 to 10,

quad

n6 and n7 are 1,

quad

X_ {1} is -WC (O) - where W is sulfur,

quad

R 5, R 5 'and R 6' are H, R 6 is NHCOCH 3.

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They are preferred compounds of formula (I) according to The present invention the following:

38

380

Examples of "alkylene C 1 -C 20 linear or branched "include, but not limited to, methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and Similar.

As indicated above, the invention also includes pharmaceutically acceptable salts of compounds of formula (I) and stereoisomers thereof.

Examples of salts pharmaceutically Acceptable are those with inorganic bases, such as hydroxides  of sodium, potassium, calcium and aluminum, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, Piperidine and other acceptable organic amines.

The compounds according to the present invention, when they contain a salifiable nitrogen atom in the molecule, they can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.

Examples of acceptable organic acids Pharmaceuticals are: oxalic, tartaric, maleic, succinic acids, citric. Examples of pharmaceutical acceptable inorganic acids they are: nitric, hydrochloric, sulfuric, phosphoric acids. Be They prefer salts with nitric acid.

The compounds of the invention that have one or more asymmetric carbon atoms can exist as enantiomers optically pure, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. Within the object of the invention there are also all possible isomers, stereoisomers and their mixtures of the compounds of formula (I).

The compounds and compositions herein invention can be administered by any system of available and effective administration including but not limited to, orally, orally, parenterally, by inhalation sprayer, by topical application, by injection, transdermally or rectally (for example, through the use of suppositories) in unit formulations of Dosage containing vehicles, adjuvants and carriers conventional non-toxic pharmaceutically acceptable.

The parenteral route includes injections subcutaneous, intravenous, intramuscular, intrasternal or An infusion technique.

Solid dosage forms for oral administration may include for example capsules, tablets, pills, powders, granules and gel. In such forms of solid dosage, the active compounds can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such a dosage form may also comprise, as a practice normal, an additional substance other than an inert diluent, for example, a lubricating agent such as stearate magnesium.

Injectable preparations may be formulated, by example sterile injectable oil or aqueous suspensions, according to the known technique using suspending agents, agents suitable humectants and / or dispersing agents.

The composition of this invention may include also conventional excipients, that is, organic substances or inorganic acceptable pharmaceuticals that do not react so harmful with active compounds.

The doses of nitroxiderivatives of blockers β-adrenergic agents can be determined by a conventional clinical technique and are at the same intervals or lower than those described for available compounds commercially as reported in: Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N.J., 58th Ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20th Ed.

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Experimental part: synthesis procedure

The compounds of the invention can synthesized as shown in schemes 1 to 6. The compounds of general formula (I) A- (Y-ONO2) s, defined in the Schemes 1-3 as compounds of formula D, in the that s is 1, Y is as defined above and A is a remainder of β-adrenergic blocker of formula (II), where Z is -C (O) - and Z1 is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt of the they can be prepared as outlined in the diagrams 1-3.

Scheme one

39

The compounds of formula (i) in which R1, R2, Z and Y are as defined above, P_ {1} is an amine protecting group such as ester tert-butyloxycarbonyl (t-Boc) and X 3 is a halogen atom preferably Cl, Br and I, it convert into compounds of formula (L) in which R 1, R 2, P_ {1}, Z and Y are as defined above, by reaction with AgNO 3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, an excess is preferably used molar of silver nitrate and the reaction is carried out, in darkness, at a temperature from room temperature to boiling temperature of the solvent. The compounds of formula (L) become the compounds of formula (D) by deprotecting the amine group (a strong acid, such as HCl in dioxane or trifluoroacetic acid, to remove a carbamate from t-butyl). Other preferred procedures for Remove amine protecting groups are those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The compounds of formula (H) in which R 1, R 2, Z, P 1 and Y are as defined above, they become the esters of formula (i) in which R1, R2, Y, Z, X3 and P1 are as defined above, by reaction with an appropriate acid (Q1) of formula X 3 -Y-COOH in which Y and X_ {3} are as defined above. The reaction is usually carried out in an organic solvent inert such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a hydrocarbon polyhalogenated aliphatic at a temperature from 0ºC to 50ºC in presence of a dehydrating agent such as DCC dicyclohexylcarbodiimide or hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide  (EDAC HCl) with a catalyst, such as 4-N, N-dimethylaminopyridine (DMAP)

The compounds of formula (H) in which R1, R 2 and P 1 are as defined above, they can Obtained by deprotecting the hydroxyl group of the compounds of formula (G) in which R 1, R 2 are as defined above and P is a hydroxyl protecting group such as silyl ethers, such as trimethylsilyl or tert-butyl dimethylsilyl and the described in T. W. Greene "Protective groups in organic synthesis ", Harvard University Press, 1980. The fluoride ion is the preferred procedure to remove the silyl protecting group ether.

The compounds of formula (G) in which R1, R2, P and P1 are as defined above, can be obtained by reacting the compounds of formula (F) wherein R_ {1}, R2 and P are as defined above with a suitable amine protecting group (P1) such as described above. The alcohol group of the compounds of formula (A) in which R 1, R 2 are as defined above, it is protected to provide the compounds of formula (F) in which R 1, R 2 are as They were defined above. Preferred protecting groups for the alcohol moiety are silyl ethers, such as trimethylsilyl or tert-butyl dimethylsilyl.

Compounds (A) in which R1, R2 are as defined above are available commercially, the acids of formula X_ {3} -Y-COOH where X_ {3} is as defined above, they are available commercially

Scheme 2

40

The compounds of formula (B) in which R1, R2, Z, Y are as defined above and X_ {3} is a halogen atom, such as Cl, Br and I, become compounds of formula (D) in which R 1, R 2, Z and Y are such as defined above, by reaction with AgNO 3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, preferably a molar excess of nitrate is used of silver and the reaction is carried out, in darkness, at a temperature from room temperature and the temperature of boiling solvent.

The compounds of formula (B) in which R1, R2, Z, Y and X3 are as defined above they can be obtained by reacting compounds of formula (A) with an appropriate acid chloride (Q) of the formula X_ {3} -Y-C (O) Cl, in which X 3 is chosen from chlorine, bromine, and Y is as it is defined above. The ester formation reaction is carried carried out in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in the presence of a base such as triethylamine, pyridine at a temperature from room temperature and 50 ° C. The reaction is completed within a period of time from 30 minutes up to 24 hours

Alternatively, the compounds of formula (B) they can be obtained by reacting a compound of formula (A) with an acid (Q1) of formula X_ {3} -Y-C (O) OH in presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or hydrochloride N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDAC) and a catalyst, such as N, N-dimethylaminopyridine. The reaction is carried out. in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from 0ºC and 50ºC. The reaction is completed in the term from a time interval from 30 minutes to 36 hours.

The compounds of formula (Q1), in which X 3 is a halogen atom, are they commercially available or can be obtained from the available hydroxylic acid commercially corresponding by well known reactions, for example by reaction with thionyl chloride or oxalyl, halides of P III or P V in inert solvents such as toluene, chloroform, DMF, etc.

Compounds (A) in which R1, R2 are as defined above are available commercially

Scheme 3

41

Alternatively, the compounds of formula (D) They can be obtained as described below. The compounds of formula A are converted into the ester (D) by reaction of the alcohol group with a nitroxy derivative, which contains a activated acylating group, of formula Cl (O) C-Y-ONO2. Nitroxyl compounds can be obtained from the corresponding alcohols of formula Cl (O) C-Y-OH by reaction with nitric acid and acetic anhydride in a range of temperature from -50ºC to 0ºC or from derivatives of corresponding halogen of formula Cl (O) C-Y-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile, tetrahydrofuran. Preferably a molar excess of silver nitrate and the reaction is carried out, in darkness, at a temperature from the boiling temperature and the room temperature. The reaction is completed within one Time interval from 30 minutes to 3 days.

The compounds of general formula (I) A- (Y-ONO2) s, defined in the Scheme 4 as compounds of formula (D1), in which s is 1, Y is as defined above and A is a blocker moiety β-adrenergic of formula (II), in which Z is -C (O) O- and Z1 is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt of the they can be prepared as outlined in scheme 4.

Scheme 4

42

The compounds of formula (B1) in which R 1, R 2, Y are as defined above and X 3 is a halogen atom, such as Cl, Br and I, become in compounds of formula (D1) in which R 1, R 2 and Y are as defined above, by reaction with AgNO 3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, an excess is preferably used molar of silver nitrate and the reaction is carried out, in darkness, at a temperature from room temperature and boiling temperature of the solvent.

The compounds of formula (A) in which R1 and R2 are as defined above they become the compounds (B1) by reaction with a compound (Q2) appropriate that has the formula X_ {3} -Y-OC (O) Cl in which X_ {3} is Cl, Br or I, and Y is as defined previously. The reaction is generally carried out in presence of a base in a non-polar or aprotic polar solvent such as THF or CH 2 Cl 2 at temperature intervals between 0ºC-65ºC or in a double phase system of H2O / Et2O at temperatures ranging from 20ºC-40ºC. The compounds of formula (Q2) are commercially available or can be obtained from corresponding alcohols by reaction with triphosgene in presence of an organic base.

The compounds of general formula (I) A- (Y-ONO2) s, defined in the scheme 5 as compounds of formula (D), in which s is 1, Y is as defined above and A is a blocker moiety β-adrenergic of formula (II), in which Z is

43

in which R 'and R' 'are as defined above and Z1 is H, the enantiomers, diastereoisomer and pharmaceutically acceptable salts of the they can be prepared as outlined in the scheme 5:

Scheme 5

44

The compounds of formula (i) in which R1, R2, Z and Y are as defined above, P_ {1} is an amine protecting group such as ester tert-butyloxycarbonyl (t-Boc) and X 3 is a halogen atom such as Cl, Br and I, become in compounds of formula (L) in which R 1, R 2, P 1, Z and Y are as defined above, by reaction with AgNO 3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, an excess is preferably used molar of silver nitrate and the reaction is carried out, in darkness, at a temperature from room temperature and boiling temperature of the solvent. The compounds of formula (L) become the compounds of formula (D) by deprotecting the amine group (a strong acid, such as HCl in dioxane or trifluoroacetic acid, to remove a carbamate from t-butyl). Other preferred procedures for Eliminate amino protecting groups are those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The compounds of formula (i) in which R 1, R 2, Y, X 3, Z and P 1 are as defined  previously, they can be obtained by reacting the compounds of formula (M) in which R 1, R 2, P 1, R ', R' 'and X 3 they are as defined above, with an acid (Q1) of formula X 3 -Y-COOH in which X 3 is a halogen atom and Y is as defined previously. The reaction is carried out in a solvent. inert organic such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a hydrocarbon polyhalogenated aliphatic at a temperature from 0ºC and 50ºC in presence of a dehydrating agent such as DCC dicyclohexylcarbodiimide or hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide  (EDAC HCl) with a catalyst, such as 4-N, N-dimethylaminopyridine (DMAP)

The reaction is completed within one Time interval from 30 minutes to 24 hours.

The compounds of formula (M) in which R1, R2, P1, R ', R' 'and X3 are as defined previously, they can be obtained by reacting compounds of formula (H) with an acyl compound (S) of formula X_ {3} -C (R ') (R' ') - OC (O) X_ {3} in which X 3 is a halogen atom. The reaction takes conducted in the presence of an organic or inorganic base in a solvent polar such as DMF, THF, acetonitrile at a temperature in the range from -5ºC to 60ºC or in a double phase system according to procedures well known in the literature.

The amino group of the compounds (A) is protected to provide the compounds of formula (H) in which P1 it is a suitable amine protecting group such as ester tert-butyloxycarbonyl (t-Boc). Compounds (S) are commercially available.

The compounds of general formula (I) A- (Y-ONO2) s, defined in the Scheme 6 as compounds of formula (E), in which s is 2, Y is as defined above and A is a blocker moiety β-adrenergic of formula (II), in which Z1 and Z are -C (O) -, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can synthesized as shown in scheme 6.

Scheme 6

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Four. Five

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The compounds of formula (C) in which R1, R2, Z, Z1 and Y are as defined above and X 3 is a halogen atom, such as Cl, Br and I, become in compounds of formula (E) in which R1, R2, Z and Y are as defined above, by reaction with AgNO 3 in a suitable organic solvent such as acetonitrile, tetrahydrofuran, an excess is preferably used molar of silver nitrate and the reaction is carried out, in darkness, at a temperature from room temperature and boiling temperature of the solvent.

The compounds of formula (C) in which R1, R2, Z, Z1, Y and X3 are as defined previously they can be obtained by reacting compounds of formula (A) with an appropriate acid chloride (Q) of formula X_ {3} -Y-C (O) Cl, in which X_ {3} is chosen from chlorine, bromine, and Y is as defined previously. The reaction is carried out in an organic solvent inert such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in the presence of a base such as triethylamine, pyridine at a temperature from room temperature and 50 ° C. The reaction is completed within a time interval from 30 minutes to 24 hours. How alternatively the compounds of formula (C) can be obtained by reaction of compounds of formula (A) with an acid (Q1) of formula X_ {3} -Y-COOH in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or hydrochloride N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide  (EDAC) and a catalytic amount of N, N-dimethylaminopyridine. The reaction takes conducted in an inert organic solvent such as N, N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from 0ºC and 50ºC. The reaction is completed within a time interval from 30 minutes to 36 hours.

The compounds of formula (Q1), in which X 3 is a halogen atom are commercially available or can be obtained from the available hydroxylic acids commercially corresponding by well known reactions, for example by reaction with thionyl chloride or oxalyl, halides of P III or P V in inert solvents such as toluene, chloroform, DMF, etc.

Compounds (A) in which R1, R2 are as defined above are available commercially

The compounds of formula (D) can also Obtained as described below. The compounds of formula A are converted to the compounds (E) by reaction with a nitroxyl derivative of the formula Cl (O) C-Y-ONO2 that It contains an activated acylating group.

Nitroxyl compounds can be obtained at from the corresponding alcohols of formula Cl (O) C-Y-OH by reaction with nitric acid and acetic anhydride in a range of temperature from -50ºC to 0ºC or from derivatives of corresponding halogen of formula Cl (O) C-Y-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile, tetrahydrofuran. Preferably a molar excess of silver nitrate and the reaction is carried out, in darkness, at a temperature from the boiling temperature and ambient temperature The reaction is completed within one Time interval from 30 minutes to 3 days.

Examples

The following non-limiting examples describe additionally and allow those of ordinary skill in the art Carry out and use the present invention.

Example 1 Maleate salt (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanoate  4- (nitroxymethyl) benzoic acid

46

1st. (S) -1 - [(1,1-Dimethyl ethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanoate 4- (chloromethyl) benzoic acid

To a solution of timolol (3.5 g, 11 mmol) in chloroform (200 ml) acid was added 4-chloromethylbenzoic acid (1.9 g, 11 mmol), EDAC (3.16 g, 16.5 mmol) and N, N-dimethylaminopyridine (amount catalytic). The reaction was stirred for 12 hours at temperature. ambient. The solution was washed with water, dried over sulfate. sodium and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with chloroform / isopropanol 10 / 0.5 giving 3 g of the title compound Like a white powder

1 B. (S) -1 - [(1,1-Dimethyl ethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanoate of 4- (nitroxymethyl) benzoic acid

A solution of the product of the example was stirred 1a (1 g, 2.1 mmol) and silver nitrate (0.71 g, 4.21 mmol) in acetonitrile (50 ml) at 60 ° C, in the dark, for 36 hours. Be The precipitate (silver salts) was removed by filtration and evaporated the solvent in vacuo. The residue was treated with chloroform and Water. The organic phase was dried over sodium sulfate and evaporated the solvent The residue was purified by chromatography of fast resolution, eluting with chloroform / isopropanol 10 / 0.5 giving 0.6 g of the title compound as a soft powder.

1 C. Maleate salt (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanoate  4- (nitroxymethyl) benzoic acid

To a solution of the product of example 1b (0.6 g, 1.2 mmol) in acetone (100 ml) maleic acid was added (0.14 g, 1.2 mmol). The reaction was stirred at room temperature. for 1 hour. The precipitate was filtered, washed with acetone and dried under vacuum providing 0.6 g of the title compound as a white powder

P.f. = 160 ° C.

1 H NMR (CDCl 3) δ (ppm): 7.99 (2H, d); 7.42 (2H, d); 5.93 (2H, s); 5.87 (1 H, m); 5.46 (2H, s); 4.82 (1H, dd); 4.71 (1H, dd); 3.73 (4H, m); 3.44 (4H, m); 1.49 (9H, s).

Example 2 (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propa- 4- (nitroxymethyl) benzoic acid noate

47

2nd. (S) -1 - [(1,1-Dimethylethyl) [(4-chloromethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propa- 4- (chloromethyl) benzoic acid noate

To a solution of timolol hydrochloride (8 g, 22.66 mmol) in chloroform (130 ml) was added dropwise 4-chloromethylbenzoyl chloride mixture (4.28 g, 22.66 mmol) and triethylamine (6.2 ml, 44.66 mmol) in chloroform (70 ml) The reaction was stirred for 24 hours at room temperature. The solution was treated with water and diethyl ether, the phases were dried organic over sodium sulfate and concentrated under pressure reduced The residue was purified by chromatography of fast resolution, eluting with chloroform / isopropanol 10 / 0.3 giving 3 g of the title compound as a powder.

2b (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propanoate  4- (nitroxymethyl) benzoic acid

A solution of the product of the example was stirred 2a (1.5 g, 2.4 mmol) and silver nitrate (1.23 g, 7.2 mmol) in acetonitrile (100 ml) at 60 ° C, in the dark, for 36 hours. Be The precipitate (silver salts) was removed by filtration and concentrated the filtrate. The residue was treated with chloroform and water and The organic phase was dried over sodium sulfate and concentrated to reduced pressure The residue was purified by chromatography of fast resolution eluting with chloroform / isopropanol 10 / 0.2 giving 0.95 g of the title product as a yellow powder.

P.f. = 44-46 ° C.

1 H NMR (CDCl 3) δ (ppm): 7.95 (2H, d); 7.50 (2H, d); 7.38 (4H, s); 5.79 (1 H, m); 5.75 (2H, s), 5.74 (2H, s); 4.50 (1H, dd); 4.30 (1H, dd); 3.95 (1H, dd); 3.85 (1H, dd); 3.59 (4H, m); 3.34 (4H, m); 1.60 (9H, s).

Example 3 (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propanol

48

3rd. (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propan-1- tert-butyldimethylsilyl   ether

To a solution of timolol (2 g, 6.32 mmol) in N, N-dimethylformamide (10 ml) was added chloride of tert-butyldimethylsilyl (1.15 g, 7.58 mmol) e imidazole (1 g, 15.8 mmol). The reaction was stirred for 2 hours at room temperature. The solution was concentrated under reduced pressure. and the residue was purified by resolution chromatography rapid eluting with chloroform / isopropanol 10 / 0.3 giving 1.5 g of title compound.

3b (S) -1 - [(1,1-Dimethylethyl) [(4-chloromethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propan-1-tert-butyldimethylsilyl  ether

To a solution of the product of example 3a (0.7 g, 1.62 mmol) in chloroform (50 ml) was added 4-chloromethylbenzoyl (0.46 g, 2.44 mmol) and triethylamine (0.39 ml, 2.44 mmol). The reaction was stirred for 24 hours at room temperature. The solution was treated with water and diethyl ether, the organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 7/3 giving the product of title (0.7 g).

3c. (S) -1 - [(1,1-Dimethylethyl) [(4-chloromethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propanol

To a solution of the product of example 3b (0.6 g, 1.03 mmol) in tetrahydrofuran (50 ml) cooled to 0 ° C, is he added a solution of tetrabutylammonium fluoride in 1 M tetrahydrofuran (0.54 ml, 2.05 mmol). The reaction was stirred. for 30 minutes at room temperature. The solution under reduced pressure and the residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 1/1 giving 0.2 g of title product.

3d. (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propanol

A solution of the product of the example was stirred 3c (0.15 g, 0.32 mmol) and silver nitrate (0.11 g, 0.64 mmol) in acetonitrile (50 ml) at 65 ° C, in the dark, for 32 hours. Be The precipitate (silver salts) was removed by filtration and concentrated the filtrate. The residue was treated with methylene chloride and water and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with n-hexane / ethyl acetate 45/65 providing 0.65 g of the title compound as a white powder.

P.f. = 50-54 ° C.

1 H NMR (CDCl 3) δ (ppm): 7.40 (4H, s); 5.44 (2H, s); 4.33-4.18 (3H, m), 3.79 (4H, dd); 3.64-3.50 (2H, m); 4.46 (4H, dd); 3.00 (1 H, s); 1.53 (9H, s).

Example 4 CGMP measurements in the rat PC12 cell line

The cGMP contributes to the function and interaction of several vascular cell types and their dysfunction is involved in major cardiovascular diseases such as hypertension, diabetic complications, atherosclerosis and tissue infarction. By Therefore, the degree of cGMP formation caused by the compounds of the inventions in the pheochromocytoma cell line of rat (PC12).

Compounds under test

1) Timolol (original compound)

2) (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-Morpholinyl) -1,2,5-thiadiazol-3-yl ] oxy] -2-propa-
4- (nitroxymethyl) benzoic acid noate (compound of example 1)

3) (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-Morpholinyl) -1,2,5-thiadiazol-3-yl ] oxy] -2-propa-
4- (nitroxymethyl) benzoic acid noate (compound of example 2)

4) (S) -1 - [(1,1-Dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl ] oxy] -2-propa-
nol (example compound 3)

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Process

The cells were maintained at 37 ° C in DMEM medium enriched with 10% horse serum and 5% fetal bovine serum under 5% CO2 atmosphere. At the time of the experiments, the cells were washed with Hank's balanced saline solution (HBSS) supplemented with 0.05% ascorbic acid and pre-incubated in the same buffer for 10 min. in a floating water bath. After the preincubation stage, the cells were exposed during another 45 min. at control conditions or at concentrations crescents of test compounds ranging from 0.1 µM and 25 µM, in the presence of the phosphodiesterase inhibitor, IBMX (100 µM) and the guanilil NO independent activator soluble cyclase, YC-1 (20 µM). The reaction by removing the incubation buffer and the consecutive addition of 100 µl of absolute ethanol. Then evaporated the organic extracts to dryness and dissolved residues in aqueous buffer for quantitative determination of intracellular cGMP levels using the immunoassay kit cGMP enzyme.

The results obtained reported in the table 1 are expressed as EC50 (µM) and Emax effectiveness (% of vehicle). As shown in the table, the nitro derivatives of Timolol caused a steady increase in cGMP formation intracellular in the PC12 cell line. Conversely, this effect does not It was shared by the original compound.

TABLE 1 Nitroxiderivative effects of timolol and timolol on the formation of GAMPc in PC12 cells

49

Claims (49)

1. A compound of general formula (I) A- (Y-ONO2) s and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, in which s is an integer equal to 1 or 2; A is selected from the following remains of β-adrenergic blockers of formula (II):

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fifty

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in the that R_ {1} is selected from the constituted group by:

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51 52 R2 is selected from the group consisting of: -CH (CH 3) 2, -C (CH 3) 3 or

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53 when the radical R_ {has} chosen from the formulas (IIo), (IIp), (IIt), (IIu), (IIv), (IIy) or (IIz), R2 is -CH (CH 3) 2; when the radical R_ {1} has been chosen from the formulas (IIq), (IIs) or (IIw), R2 is -C (CH 3) 3; when the radical R1 is (IIr), R2 is (IIIc); Z is H or is a group that can join Y selected from the group consisting of: -C (O) -, -C (O) O- or

           \ vskip1.000000 \ baselineskip
        

54 in which R 'and R' 'are equal or different, and are H or linear C 1 -C 4 alkyl or branched; Z_ {1} is H or a group -C (O) - which can join Y; with the proviso that when s of formula (I) is 1, Z or Z1 is H; And it is a bivalent radical that has the following meaning: to)

-

\ vtcortauna linear or branched C 1 -C 20 alkylene which is optionally substituted with one or more of the substituents selected from the group consisting of halogen, hydroxyl, -ONO 2 or T atoms, wherein T is -OC (O) (C 1 -C 10 alkyl) - ONO 2, -O (C 1 -C 10 alkyl) - ONO 2;

b)

-

\ vtcortauna cycloalkylene with 5 to 7 carbon atoms in the cycloalkylene ring, the ring being optionally substituted with T 1 side chains, wherein T 1 is linear or branched alkyl with from 1 to 10 carbon atoms;

           \ newpage
        

C) 55

quad

in which:

quad

n is an integer from 0 to 20, and n1 is a integer from 1 to 20;

quad

n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1;

quad

R 3 and R 4 are independently selected of H or CH 3;

quad

Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20;

quad

X_ {1} is -WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH;

quad

with the condition of:

-

\ vtcortauna when s of formula (I) is 1, Z is - (CO) - and in formula (IV) of the bivalent radical Y n2, n3, n4, n5 are equal to 0 then n is 0 and n1 is 1;

-

\ vtcortauna when s of formula (I) is 1, Z is - (CO) - and in formula (IV) of the bivalent radical Y n2, n3, n5 are equal to 0, n4 is 1 then n and n1 are different from 1;

d) 56

quad

in which:

quad

n1 is an integer from 1 to 20;

quad

X_ {1} is WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH;

quad

n6 is an integer from 1 to 20,

quad

n7 is an integer from 0 to 20,

quad

R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the link between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' are absent;

quad

with the proviso that when Y is selected from the bivalent radicals mentioned in c) -d), the group -ONO_ {2} is joined to a group - (CH 2) n 1 -;

quad

with the proviso that when s of formula (I) is 1 and Z is - (CO) - so the bivalent radical Y does not have the meanings in a), b) and d);

           \ newpage
        

and)

           \ vskip1.000000 \ baselineskip
        

57

           \ vskip1.000000 \ baselineskip
        

quad

where X_ {2} is O or S,

quad

n10a, n10 and n12 are integers independently selected from 0 to 20,

quad

n11 is an integer from 0 to 6,

quad

R 11 is H, CH 3 or group nitroxyl;

quad

with the proviso that when in formula (I) s is 1, in formula (II) Z is - (CO) -, in formula (VI) of bivalent radical Y n10a, n10, n12 are equal to 1 then X no it can be an oxygen atom;

           \ vskip1.000000 \ baselineskip
        

F)

           \ vskip1.000000 \ baselineskip
        

58

           \ vskip1.000000 \ baselineskip
        

quad

in which:

quad

n8 is an integer from 0 to 10;

quad

n9 is an integer from 1 to 10;

quad

R 9, R 10, R 8, R 7 are the same or different, and are H or linear C 1 -C 4 alkyl or branched;

quad

in which the group -ONO_ {2} is united to

           \ vskip1.000000 \ baselineskip
        

59

           \ vskip1.000000 \ baselineskip
        

quad

in which n9 is as defined previously;

           \ newpage
        

quad

Y2 is a 5 or 6 member ring saturated, unsaturated or aromatic heterocyclic, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and select from the group consisting of:

60 61 2. A compound and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, wherein s is equal to 1 and Z1 is H. 3. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, wherein Z is -C (O) -. 4. A compound and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3, wherein And it is 62 in the that n, n2, n3, n4 and n5 are equal to 0 n1 is an integer equal to 1; 5. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3, wherein And it is 63 in the that n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10, Y1 is - (CH2) na -CH = CH- in which na is 0, X_ {1} is -WC (O) - where W is oxygen and X1 is attached to the phenyl ring through the [C] 4, R 4 is CH 3 and the group (OR 4) is attached to the phenyl ring through [C] 3. 6. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3, wherein And it is 64 in the that X_ {2} is O or S, n10a, n10 and n12 are integers independently selected from 2 to 20; n11 is an integer from 0 to 6; R 11 is H, CH 3 or a group nitroxyl; R 11a is CH 3 or a nitroxyl group. 7. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, wherein Z is -C (O) O-. 8. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 7, wherein

           \ newpage
        

And it is an alkylene C_ {1} -C_ {linear or branched which is optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxyl, -ONO2 or T, wherein T is -OC (O) (alkyl C_ {1} -C_ {10}) - ONO_ {2}, -O (alkyl C_ {1} -C_ {10}) - ONO_ {2}. 9. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 8, wherein And it is an alkylene C 1 -C 10 linear or branched. 10. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 7, wherein And it is 65 in the that n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1; R 3 and R 4 are selected independently of H or CH 3; Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20; X_ {1} is WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. 11. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 10, wherein n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10, Y 1 is CH 2. 12. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 7, wherein And it is 66 in the that X_ {2} is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R 11 is H, CH 3 or a group nitroxyl; R 11a is CH 3 or a nitroxyl group. 13. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 12, wherein And it is 67 in the that X_ {2} is O or S, n10a and n11 are 0, n12 is 1, and R 11 is H; in which the group -ONO_ {2} is attached to the group - (- CH2) n12 -. 14. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 7, wherein And it is 68 in the that: n1 is an integer from 1 to 20; X_ {1} is -WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of: H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the link between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' are absent. 15. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 2, wherein Z is 69 16. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 15, wherein And it is an alkylene C_ {1} -C_ {linear or branched which is optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxyl, -ONO2 or T, wherein T is -OC (O) (alkyl C_ {1} -C_ {10}) - ONO_ {2}, -O (alkyl C_ {1} -C_ {10}) - ONO_ {2}. 17. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 16, wherein Y is an alkylene C 1 -C 10 linear or branched. 18. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 15, wherein And it is 70 in the that n is an integer from 0 to 20, n1 is an integer from 1 to 20, n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1; R 3 and R 4 are selected independently of H or CH 3; Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20; X_ {1} is -WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. 19. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 18, wherein n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10, Y 1 is CH 2. 20. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, wherein Z and Z1 are -CO)-. 21. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 20, wherein And it is an alkylene C_ {1} -C_ {linear or branched which is optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxyl, -ONO2 or T, wherein T is -OC (O) (alkyl C_ {1} -C_ {10}) - ONO_ {2}, -O (alkyl C_ {1} -C_ {10}) - ONO_ {2}. 22. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 21, wherein Y is an alkylene C 1 -C 10 linear or branched. 23. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 20, wherein And it is 71 in the that n is an integer from 0 to 20, n1 is an integer from 1 to 20, n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1, R 3 and R 4 are selected independently of H or CH 3; Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20; X_ {1} is WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. 24. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 23, wherein n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10, Y 1 is CH 2. 25. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 23, wherein n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10, Y1 is - (CH2) na -CH = CH- in which na is 0, X_ {1} is WC (O) - where W is oxygen and X1 is attached to the phenyl ring through [C] 4, R 4 is CH 3 and the group (OR 4) is attached to the ring phenyl through [C] 3. 26. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 20, wherein

           \ newpage
        

And it is

           \ vskip1.000000 \ baselineskip
        

72

           \ vskip1.000000 \ baselineskip
        

in which X_ {2} is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R 11 is H, CH 3 or a group nitroxyl; R 11a is CH 3 or a nitroxyl group. 27. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 26, wherein And it is

           \ vskip1.000000 \ baselineskip
        

73

           \ vskip1.000000 \ baselineskip
        

in the that X_ {2} is O or S, n10a and n11 are 0, n12 is 1, R 11 is H; in which the group -ONO_ {2} is attached to the group - (CH2) n12 -. 28. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 20, wherein

           \ newpage
        

And it is

           \ vskip1.000000 \ baselineskip
        

74

           \ vskip1.000000 \ baselineskip
        

in the that: n1 is an integer from 1 to 20; X_ {1} is -WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of: H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the bond between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' They are absent. 29. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 28, wherein n1 is an integer from 1 to 10, n6 and n7 are 1; X_ {1} is WC (O) - where W is sulfur, R 5, R 5 'and R 6' are H, R 6 is NHCOCH 3, with the proviso that the group -ONO_ {2} is joined to the group - (CH2) n1 -. 30. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1, wherein s is 1, Z is H and Z1 are -CO)-. 31. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 30, wherein And it is an alkylene C_ {1} -C_ {linear or branched which is optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxyl, -ONO2 or T, wherein T is -OC (O) (alkyl C_ {1} -C_ {10}) - ONO_ {2}, -O (alkyl C_ {1} -C_ {10}) - ONO_ {2}. 32. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 31, wherein Y is an alkylene C 1 -C 10 linear or branched. 33. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 30, wherein

           \ newpage
        

And it is

           \ vskip1.000000 \ baselineskip
        

75

           \ vskip1.000000 \ baselineskip
        

in the that n is an integer from 0 to 20, n1 is an integer from 1 to 20; n2, n3, n4 and n5 are equal whole numbers or different from each other, equal to 0 or 1; R 3 and R 4 are selected independently of H or CH 3; Y 1 is -CH 2 - or - (CH 2) na -CH = CH- in which na is a integer from 0 to 20; X_ {1} is -WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. 34. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 33, wherein n2, n3, n4, n5 are equal to 0, n1 is 1, n is an integer from 0 to 10, Y 1 is CH 2. 35. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 33, wherein n, n2, n5 are 1, n3 and n4 are equal to 0, n1 is an integer from 1 to 10, Y1 is - (CH2) na -CH = CH- in which na is 0, X_ {1} is WC (O) -, in which W is oxygen and X1 is attached to the phenyl ring through the [C] 4, R 4 is CH 3 and the group (OR 4) is attached to the phenyl ring through [C] 3. 36. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 30, wherein

           \ newpage
        

And it is

           \ vskip1.000000 \ baselineskip
        

76

           \ vskip1.000000 \ baselineskip
        

in which X_ {2} is O or S, n10a, n10 and n12 are integers independently selected from 0 to 20; n11 is an integer from 0 to 6; R 11 is H, CH 3 or a group nitroxyl; R 11a is CH 3 or a nitroxyl group. 37. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 36, wherein And it is

           \ vskip1.000000 \ baselineskip
        

77

           \ vskip1.000000 \ baselineskip
        

in which X_ {2} is O or S, n10a and n11 are 0, n12 is 1, R 11 is H, in which the group -ONO_ {2} is attached to the group - (CH2) n12 -. 38. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 30, wherein

           \ newpage
        

And it is

           \ vskip1.000000 \ baselineskip
        

           \ vskip1.000000 \ baselineskip
        

78

           \ vskip1.000000 \ baselineskip
        

in the that: n1 is an integer from 1 to 20; X_ {1} is WC (O) - or -C (O) W-, in which W is oxygen, sulfur or NH. n6 is an integer from 1 to 20, n7 is an integer from 0 to 20, R 5 and R 5 'R 6 and R 6' are independently selected from the group consisting of: H, CH 3, OH, NH 2, NHCOCH 3, COOH, CH 2 SH and C (CH 3) 2 SH; when the bond between carbons C A and C B is a double bond R 5 and R 6 or R 6 'and R 5' They are absent. 39. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 38, wherein n1 is an integer from 1 to 10, n6 and n7 are 1; X_ {1} is -WC (O) - where W is sulfur; R 5, R 5 'and R 6' are H, R 6 is NHCOCH 3; with the proviso that the group -ONO_ {2} is attached to the - (CH 2) n 1 -. 40. Compounds and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 and claim 4, wherein Compounds are:

           \ vskip1.000000 \ baselineskip
        

79

           \ newpage
        

41. Compounds and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 20 and claim 24, wherein the Compounds are: 80 42. Compounds and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 30 and claim 34, wherein Compounds are: 81 43. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to the claim 1 and claim 4, which is maleate salt of (S) -1 - [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanoate  of 4- (nitroxymethyl) benzoic acid. 44. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to the claim 1 and claim 24, which is (S) -1 - [(1,1-dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propanoate  of 4- (nitroxymethyl) benzoic acid. 45. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to the claim 1 and claim 34, which is (S) -1 - [(1,1-dimethylethyl) [(4-nitroxymethyl) benzoyl] amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy ] -2-propanol. 46. A compound of formula (I) and / or enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in any of the claims 1 to 45, for use as a medicine. 47. Use of a compound of formula (I) and / or enantiomers, diastereoisomers and pharmaceutically acceptable salts  thereof as defined in any of the claims 1 to 45, to prepare a drug that can be used in the treatment or prophylaxis of hypertension, vascular diseases and cardiovascular. 48. Use of a compound of formula (I) and / or enantiomers, diastereoisomers and pharmaceutically acceptable salts  thereof as defined in any of the claims 1 to 45, to prepare a drug that can be used in the treatment of glaucoma and elevated intraocular pressure. 49. A pharmaceutical composition comprising a compound of formula (I) and / or enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined. in any one of claims 1 to 45 and a vehicle pharmaceutically acceptable.